N-[3-(1H-benzimidazol-2-yl)phenyl]-N'-(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)thiourea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: N-[3-(1H-benzimidazol-2-yl)phenyl]-N'-(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)thiourea
• 英文别名: S-[[3-(1H-benzimidazol-2-yl)phenyl]carbamoylamino] 2,3-dihydro-1,4-benzodioxine-6-carbothioate
• 化学式: C₂₃H₁₈N₄O₄S
• 分子量: 446.486
• InChiKey: HLKFFGCUFHDFOU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  131
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  sodium hydrogen sulfate 、 间硝基苯甲醛 以 N,N-二甲基甲酰胺 为溶剂， 以39%的产率得到5-(1H-苯并[d]咪唑-2-基)-2-甲基苯胺
  参考文献：
  名称：

  Pharmaceutical compositions comprising Neuropilin inhibitors, and their use for the prevention and/or treatment of angiogenic disorders and cancers

  摘要：

  本发明涉及一种包含一般式(I)化合物的药物组合物，其中- Z1为S或O，优选S；- -Z2-为-NRa-，其中Ra为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺，优选Ra为H；-N=；O；S；-CRb=，其中Rb为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、Cl、Br、I、F，优选H；-CHRc-，其中Rc为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、Cl、Br、I、F，或-CH2-；优选-Z2-为-NH-或-N=；- R1和R2中的每一个独立地为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、Cl、Br、I、F；优选R1和R2连同N和Z2形成最终被取代的杂环，更优选为取代的氮杂环、3H-吲哚、吲哚唑、2-咪唑啉、2-吡唑啉、苯并噻唑、嘧啶、嘧啶、吡啶、吡啶啉、吡啶二唑、吡啶啉、噻唑、异噻唑、噁唑、异噁唑、喹啉、异喹啉、喹啉、1-8-萘啉、邻苯二嗪、邻苯二氮杂吡啉、邻苯二氮杂吡啉、[1,10]-邻菲啉、邻苯二甲酸咪唑啉、喹啉、三唑、三嗪、呋喃唑、6H-1,2,5-二噻二氮杂嗪、1,3,4-二噻二唑、四唑，或取代的咪唑并且更优选为苯并咪唑；- R5为H、OH、C1-4烷基、C1-4烷氧基、C1-4烯基、C1-4炔基、胺，优选R5为NH2、NO2、Cl、F、Br、I；更优选R5为H或CH3；甚至更优选R5为CH3；- R8和R9中的每一个独立地为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、Cl、Br、I、F；优选R8和R9连同形成包含5或6个原子的环，优选为包含5或6个原子的杂环，更优选为1,3-二氧杂环戊烯或1,4-二氧杂环戊烷；- R3、R4、R6、R7、R10和R11中的每一个独立地为H、OH、C1-4烷基、C1-4烷氧基、C1-4烯基、C1-4炔基、胺、NO2、F、Cl、Br、I；优选H、CH3、OCH3、OH、NH2、NO2、Cl、F、Br、I；更优选为H或CH3；甚至更优选为H，或其酯或盐；与至少一种药学上可接受的载体结合；以及将其用于抑制神经丝蛋白途径在癌症和血管生成性疾病治疗中的应用。

  公开号：

  EP2522341A1

文献信息

• [EN] PHARMACEUTICAL COMPOSITIONS COMPRISING NEUROPILIN INHIBITORS, AND THEIR USE FOR THE PREVENTION AND/OR TREATMENT OF ANGIOGENIC DISORDERS AND CANCERS<br/>[FR] COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES INHIBITEURS DE NEUROPILINE, ET LEUR UTILISATION DANS LA PRÉVENTION ET/OU LE TRAITEMENT DE TROUBLES ANGIOGÉNIQUES ET DE CANCERS
  申请人：TRAGEX PHARMA

  公开号：WO2012156289A1

  公开（公告）日：2012-11-22

  The present invention relates to a compound of general formula (I), wherein Z1 is S or O, preferably S; -Z2- is -NRa-, wherein Ra is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, preferably Ra is H; -N=; O; S; -CRb=, wherein Rb is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO2, C1, Br, I, F, preferably H; -CHRC- wherein Rc is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO2, C1, Br, I, F, or -CH2-; preferably -Z2- is -NH- or -N=; each of R1 and R2 independently is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO2, C1, Br, I, F; preferably R1 and R2 together and with N and Z2 form an heterocycle eventually substituted, provided that said heterocycle is not an indole; R5 is H, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 alkenyl, C1-4 alkynyl, amine, preferably R5 is NH2, NO2, C1, F, Br, I; more preferably R5 is H or CH3; even more preferably R5 is CH3; each of R8 and R9 independently is, H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO2, C1, Br, I, F; preferably R8 and R9 together form a cycle comprising 5 or 6 atoms, preferably an heterocycle comprising 5 or 6 atoms, more preferably a 1,3- dioxacyclopentene or a 1,4-dioxane; and - each of R3, R4, R6, R7, R10 and R11 independently is, H, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 alkenyl, C1-4 alkynyl, amine, NO2, F, C1, Br, I; preferably H, CH3, OCH3, OH, NH2, NO2, C1, F, Br, I; more preferably is H or CH3; even more preferably is H; and to a pharmaceutical composition comprising a compound of general formula (I) or esters or salts thereof, in association with at least one pharmaceutically acceptable vehicle; and to the use thereof for inhibiting the Neuropilin pathways in the treatment of cancer and of angiogenic diseases.

  本发明涉及一般式(I)的化合物，其中Z1为S或O，优选为S；-Z2-为-NRa-，其中Ra为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺，优选Ra为H；-N=；O；S；-CRb=，其中Rb为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、C1、Br、I、F，优选为H；-CHRC-，其中Rc为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、C1、Br、I、F，或-CH2-；优选-Z2-为-NH-或-N=；R1和R2各自独立为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、C1、Br、I、F，优选R1和R2一起与N和Z2形成最终可能被取代的杂环，前提是该杂环不是吲哚；R5为H、OH、C1-4烷基、C1-4烷氧基、C1-4烯基、C1-4炔基、胺，优选R5为NH2、NO2、C1、F、Br、I，更优选R5为H或CH3，甚至更优选R5为CH3；R8和R9各自独立为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、C1、Br、I、F，优选R8和R9一起形成包括5或6个原子的环，优选为包括5或6个原子的杂环，更优选为1,3-二氧杂环戊烯或1,4-二氧杂环戊烷；每个R3、R4、R6、R7、R10和R11各自独立为H、OH、C1-4烷基、C1-4烷氧基、C1-4烯基、C1-4炔基、胺、NO2、F、C1、Br、I，优选为H、CH3、OCH3、OH、NH2、NO2、C1、F、Br、I，更优选为H或CH3，甚至更优选为H；以及包含一般式(I)的化合物或其酯或盐的药物组合物，与至少一种药用可接受载体结合使用，用于抑制神经丝蛋白途径，治疗癌症和血管生成性疾病。
• PHARMACEUTICAL COMPOSITIONS COMPRISING NEUROPILIN INHIBITORS, AND THEIR USE FOR THE PREVENTION AND/OR TREATMENT OF ANGIOGENIC DISORDERS AND CANCERS
  申请人：TRAGEX PHARMA

  公开号：US20130041005A1

  公开（公告）日：2013-02-14

  The present invention relates to a compound of general formula (I), and to a pharmaceutical composition comprising a compound of general formula (I) or esters or salts thereof, in association with at least one pharmaceutically acceptable vehicle; and to the use thereof for inhibiting the Neuropilin pathways in the treatment of cancer and of angiogenic diseases.

  本发明涉及一种通式(I)的化合物，以及包含通式(I)的化合物或其酯或盐与至少一种药用载体结合的制药组合物；以及在抑制神经粘附蛋白途径治疗癌症和血管生成性疾病方面的应用。
• [EN] A NEUROPILIN ANTAGONIST IN COMBINATION WITH A P38ALPHA-KINASE INHIBITOR FOR THE TREATMENT OF CANCER<br/>[FR] ANTAGONISTE DE LA NEUROPILINE ASSOCIÉ À UN INHIBITEUR DE KINASE P38ALPHA POUR LE TRAITEMENT DU CANCER
  申请人：INST NAT SANTE RECH MED

  公开号：WO2020245210A1

  公开（公告）日：2020-12-10

  Neuropilin-1 is henceforth a relevant target in cancer treatment, however way-of-action is remains partly elusive and the development of small inhibitory molecules is therefore required for its study. Here, the inventors report that two neuropilin small-sized antagonists (NRPa-47, NRPa-48), VEGF-A165/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in triple negative breast cancer cell line (MDA-MB-231). In particular, the inventors showed for the first time, how NRPa may altered tumor cell signaling and contributed in the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. More importantly, the association of NRPa with a p38α inhibitor leads to additional and/or synergistic effect of these drugs (depending of the dose used) for significantly reducing breast cancer cell proliferation Thus, the efficient association of NRPa and p38α-kinase inhibitors are thus credible for the treatment of cancer.
• [EN] USE OF NEUROPILIN ANTAGONISTS FOR THE TREATMENT OF ENDOMETRIOSIS<br/>[FR] UTILISATION D'ANTAGONISTES DE LA NEUROPILINE POUR LE TRAITEMENT DE L'ENDOMÉTRIOSE
  申请人：INST NAT SANTE RECH MED

  公开号：WO2021105368A1

  公开（公告）日：2021-06-03

  Endometriosis is a chronic inflammatory systemic sex hormone-dependent gynecological disease, characterized by the presence and growth of endometrial tissue (glands and stroma) outside the uterine cavity, predominantly, but not exclusively, in the pelvic compartment. Here, the inventors show that the use of Neuropilin/ VEGF binding inhibitors, so called, Neuropilin antagonist (NRPa), bring new perspective to treat and cure endometriosis in women suffering thereof. NRPa alone is efficient to inhibit primary endometrial cell proliferation and apoptosis/necrosis program cell death of targeted cells. The effective NRPa concentration needed is very low (NRPa-48 IC50=1 0-7M) and is dependent of the NRPa structure. Moreover, the association of NRPa with progestogen drug increases the anti-proliferative effect. Therefore, the present invention relates to the use of neuropilin antagonists for the treatment of endometriosis.
• Pharmaceutical compositions comprising Neuropilin inhibitors, and their use for the prevention and/or treatment of angiogenic disorders and cancers
  申请人：Tragex Pharma

  公开号：EP2522341A1

  公开（公告）日：2012-11-14

  The present invention relates to a pharmaceutical composition comprising a compound of general formula (I), wherein - Z1 is S or O, preferably S; - -Z2- is -NRa-, wherein Ra is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, preferably Ra is H; -N=; O; S; -CRb=, wherein Rb is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO2, Cl, Br, I, F, preferably H; -CHRc-, wherein Rc is H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO2, Cl, Br, I, F, or -CH2-; preferably -Z2- is -NH- or -N=; - each of R1 and R2 is independently H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO2, Cl, Br, I, F; preferably R1 and R2 together and with N and Z2 form an heterocycle eventually substituted, more preferably a substituted azocine, 3H-indole, indazole, 2-imidazoline, 2-pyrazoline, benzthiazole, purine, pyrimidine, pyridine, pyridazine, pyrazine, pyrazole, thiazole, isothiazole, oxazole, isoxazole, quinoline, isoquinoline, quinoxaline, quinazoline, 1-8-naphthyridine, perimidine, [1,10]-phenantroline, phthalazine, pteridine, triazole, triazine, furazan, 6H-1,2,5-thiadiazine, 1,3,4-thiadiazole, tetrazole, or a substituted imidazole and even more preferably a benzimidazole; - R5 is H, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 alkenyl, C1-4 alkynyl, amine, preferably R5 is NH2, NO2, Cl, F, Br, I; more preferably R5 is H or CH3; even more preferably R5 is CH3; - each of R8 and R9 is independently, H, OH, alkyl, alkoxy, aryle, alkenyl, alkynyl, amine, NO2, Cl, Br, I, F; preferably R8 and R9 together form a cycle comprising 5 or 6 atoms, preferably an heterocycle comprising 5 or 6 atoms, more preferably a 1,3-dioxacyclopentene or a 1,4-dioxane; and - each of R3, R4, R6, R7, R10 and R11 is independently, H, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 alkenyl, C1-4 alkynyl, amine, NO2, F, Cl, Br, I; preferably H, CH3, OCH3, OH, NH2, NO2, Cl, F, Br, I; more preferably is H or CH3; even more preferably is H, or esters or salts thereof; in association with at least one pharmaceutically acceptable vehicle; and to the use thereof for inhibiting the Neuropilin pathways in the treatment of cancer and of angiogenic diseases.

  本发明涉及一种包含一般式(I)化合物的药物组合物，其中- Z1为S或O，优选S；- -Z2-为-NRa-，其中Ra为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺，优选Ra为H；-N=；O；S；-CRb=，其中Rb为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、Cl、Br、I、F，优选H；-CHRc-，其中Rc为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、Cl、Br、I、F，或-CH2-；优选-Z2-为-NH-或-N=；- R1和R2中的每一个独立地为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、Cl、Br、I、F；优选R1和R2连同N和Z2形成最终被取代的杂环，更优选为取代的氮杂环、3H-吲哚、吲哚唑、2-咪唑啉、2-吡唑啉、苯并噻唑、嘧啶、嘧啶、吡啶、吡啶啉、吡啶二唑、吡啶啉、噻唑、异噻唑、噁唑、异噁唑、喹啉、异喹啉、喹啉、1-8-萘啉、邻苯二嗪、邻苯二氮杂吡啉、邻苯二氮杂吡啉、[1,10]-邻菲啉、邻苯二甲酸咪唑啉、喹啉、三唑、三嗪、呋喃唑、6H-1,2,5-二噻二氮杂嗪、1,3,4-二噻二唑、四唑，或取代的咪唑并且更优选为苯并咪唑；- R5为H、OH、C1-4烷基、C1-4烷氧基、C1-4烯基、C1-4炔基、胺，优选R5为NH2、NO2、Cl、F、Br、I；更优选R5为H或CH3；甚至更优选R5为CH3；- R8和R9中的每一个独立地为H、OH、烷基、烷氧基、芳基、烯基、炔基、胺、NO2、Cl、Br、I、F；优选R8和R9连同形成包含5或6个原子的环，优选为包含5或6个原子的杂环，更优选为1,3-二氧杂环戊烯或1,4-二氧杂环戊烷；- R3、R4、R6、R7、R10和R11中的每一个独立地为H、OH、C1-4烷基、C1-4烷氧基、C1-4烯基、C1-4炔基、胺、NO2、F、Cl、Br、I；优选H、CH3、OCH3、OH、NH2、NO2、Cl、F、Br、I；更优选为H或CH3；甚至更优选为H，或其酯或盐；与至少一种药学上可接受的载体结合；以及将其用于抑制神经丝蛋白途径在癌症和血管生成性疾病治疗中的应用。